The present invention relates to an oxindole derivative useful for growth hormone releaser etc.
Various factors are related to growth in individuals. However, growth hormone should apparently be the most important factor for growing, since surplus secretion of growth hormone may result in gigantism or acromegaly, and deficiency in growth hormone may result in dwarfism. Growth hormone is known to have basic effects on the metabolic processees of the body: to increase rate of protein synthesis, to decrease rate of carbohydrate utilization, and to increase mobilization of free fatty acids and use of fatty acids for energy.
Various compounds such as arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, and insulin induced hypoglycemia are known to cause a release of growth hormone. Activities such as sleep and exercise are also known to release growth hormone. These compounds and activities indirectly cause growth hormone to be released from the pituitary by acting on the hypothalamus in various ways such as to decrease somatostatin secretion and to increase the secretion of the known secretagogue growth hormone releasing factor (GRF) or an unknown endogenous growth hormone-releasing hormone.
Providing exogenous growth hormone is used as one way to increase levels of growth hormone. The sources of growth hormone used are either from extractions of pituitary glands of cadavers or recombinant growth hormone. However, the resulting growth hormone is very expensive and the extracted products from pituitary glands have risks that diseases associated with the source of the pituitary gland could be transmitted to the recipient of the growth hormone. Growth hormone should be given by injection or by a nasal spray, because its oral administration is difficult.
Another way to increase levels of growth hormone is to administer compounds which stimulate the release of endogenous growth hormone such as GRF or its derivatives (Schoen W. R. et. al., xe2x80x9cGrowth hormone secretagoguesxe2x80x9d in Annual Reports in Medicinal Chemistry: Academic Press, Vol. 28, Chapter 19, 1993) and peptidyl compounds (U.S. Pat. No. 4,411,890). These peptides are considerably smaller than growth hormones, but are still susceptible to various proteases. Therefore, their potential for oral bioavailability is low.
WO 94/01369 discloses non-peptide compounds useful as growth hormone releasers. Though these compounds are stable under various physiological environments and applicable parenterally, intranasally or orally, these compounds have not been approaved as a drug.
J. Chem. Soc. Perkin Trans. 1, 1975-1979(1991) describes that benzodiazocine derivatives were formed by heating oxindole derivatives in the presence of acid catalyst.
Chem. Pharm. Bull., 21, 960-971(1973) describes that oxindole derivatives without any substituents on its benzene ring have analgesic and anti-inflammatory effects.
The inventors of the present invention have intensively carried out research on growth hormone releasers, and found that oxindole derivatives or prodrugs thereof, and pharmaceutically acceptable salts thereof are growth hormone releasers which are applicable as a medicine. Thus, the present invention has been accomplished.
That is, the present invention is as follows:
[1] An oxindole derivative of Formula 1 or a prodrug thereof, or a pharmaceutically acceptable salt thereof: 
xe2x80x83wherein
R1, R2, R3 and R4 are the same or different and each is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, halogen, cyano, nitro, hydroxy, optionally substituted amino, alkoxy, alkanoyl, alkoxycarbonyl, optionally substituted sulfamoyl, optionally substituted carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino or alkanoylamino, provided that all of R1, R2, R3 and R4 are not simultaneously hydrogen;
R5 is optionally substituted aryl or optionally substituted heteroaryl;
Z is xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94;
one of W1 and W2 is hydrogen, alkyl or xe2x80x94Yxe2x80x94CON(R10)R11;
the other of W1 and W2 is 
n is 1, 2 or 3; m is 0, 1, 2 or 3;
Y is single bond or C1-C3 alkylene;
R6 and R7 are the same or different and each is independently hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl; or R6 and R7 are taken together with the adjacent nitrogen atom to form optionally substituted saturated heterocyclic ring;
R8 and R9 are the same or different and each is independently hydrogen or optionally substituted alkyl; or R8 and R9 are taken together with the adjacent carbon atom to form optionally substituted cycloalkane or optionally substituted saturated heterocyclic ring;
R8 and R6 may be taken together to form C1-C5 alkylene in which case R7 is hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl, and R9 is hydrogen or optionally substituted alkyl;
R10 and R11 are the same or different and each is independently hydrogen or alkyl; or R10 and R11 are taken together with the adjacent nitrogen atom to form optionally substituted saturated heterocyclic ring.
[2] An oxindole derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof according to [1] wherein R1, R2, R3 and R4 are independently hydrogen, alkyl optionally substituted by halogen, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbamoyl, halogen, cyano, nitro, alkanoyl, alkoxycarbonyl, alkylsulfinyl or alkylsulfonyl, provided that all of R1, R2, R3 and R4 are not simultaneously hydrogen.
[3] An oxindole derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof according to [1] wherein R1, R2, R3 and R4 are independently hydrogen, trifluoromethyl, carbamoyl, halogen, 4-carbamoyl-1-butynyl, 4-alkylcarbamoyl-1-butynyl, 4-dialkylcarbamoyl-1-butynyl, 4-morpholinocarbonyl-1-butynyl, xe2x80x94Cxe2x89xa1Cxe2x80x94(CH2)kxe2x80x94Q, wherein k is 1 or 2; Q is hydroxy, alkylsulfonyl, alkanoylamino, alkylureido, 2-oxo-1-imidazolidinyl or 2-oxo-1,3-oxazolin-3-yl, provided that all of R1, R2, R3 and R4 are not simultaneously hydrogen.
[4] An oxindole derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof according to [3] wherein both of R2 and R4 are hydrogen.
[5] An oxindole derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof according to [1] wherein both of R2 and R4 are hydrogen; R1 is trifluoromethyl, chlorine or bromine; and R3 is carbamoyl, halogen, 4-carbamoyl-1-butynyl, 4-alkylcarbamoyl-1-butynyl, 4-dialkylcarbamoyl-1-butynyl, 4-morpholinocarbonyl-1-butynyl, xe2x80x94Cxe2x89xa1Cxe2x80x94(CH2)kxe2x80x94Q, wherein k and Q are as defined above.
[6] An oxindole derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof according to [1] wherein both of R2 and R4 are hydrogen; R1 is trifluoromethyl, chlorine or bromine; and R3 is carbamoyl.
[7] An oxindole derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof according to any one of [1] to [6] wherein R5 is optionally substituted phenyl or optionally substituted 2-naphthyl.
[8] An oxindole derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof according to any one of [1] to [6] wherein R5 is phenyl optionally substituted by halogen(s) and/or trifluoromethyl(s) or 2-naphthyl optionally substituted by halogen(s) and/or trifluoromethyl(s).
[9] An oxindole derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof according to any one of [1] to [8] wherein R6 and R7 are independently optionally substituted alkyl or optionally substituted cycloalkyl; or R6 and R7 are taken together with the adjacent nitrogen atom to form optionally substituted saturated heterocyclic ring.
[10] An oxindole derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof according to any one of [1] to [9] wherein one of W1 and W2 is hydrogen or xe2x80x94CONHR10; and the other of W1 and W2 is 
xe2x80x83wherein n, m, R6, R7, R8, R9 and R10 are as defined in [1].
[11] An oxindole derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof according to any one of [1] to [9] wherein one of W1 and W2 is hydrogen; and the other of W1 and W2 is 
xe2x80x83wherein p is an integer of 2 to 7; and R12 and R13 are independently optionally substituted alkyl.
[12] An oxindole derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof according to any one of [1] to [9],
xe2x80x83wherein
(1) W1 is hydrogen; and W2 is 
(2) W2 is hydrogen; and W1 is 
xe2x80x83wherein p1 is an integer of 2 to 7; p2 is an integer of 3 to 7; and R12 and R13 are independently optionally substituted alkyl.
[13] An oxindole derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof according to [11] or [12] wherein R12 and R13 are independently methyl or ethyl.
[14] An optical isomer of an oxindole derivative according to any one of [1] to [13], of which the configuration at the C-3 position is equivalent to that of (+)-1-diethylaminoethyl-4-trifluoromethyl-6-carbamoyl-3-hydroxy-3-(2-chlorophenyl)oxindole, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
[15] A medicament containing an oxindole derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof according to any one of [1] to [14] and a pharmaceutically acceptable carrier or diluent.
[16] A medicament according to [15] wherein the medicament is growth hormone releaser.
[17] An oxindole derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof according to any one of [1] to [14] for use in therapy.
[18] Use of an oxindole derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof according to any one of [1] to [14] for the production of growth hormone releaser.
[19] Method of releasing growth hormone comprising administering an oxindole derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof according to any one of [1] to [14] to a human or a non-human mammal in need thereof.
xe2x80x9cAlkylxe2x80x9d includes straight or branched C1-C6 alkyl. Typical examples are methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, pentyl, 1-methylbutyl, 2-methylbutyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 1-ethylbutyl and the like. The alkyls in xe2x80x9calkylthioxe2x80x9d, xe2x80x9calkylsulfinylxe2x80x9d, xe2x80x9calkylsulfonylxe2x80x9d and xe2x80x9calkylsulfonylaminoxe2x80x9d include the same.
xe2x80x9cAlkenylxe2x80x9d includes straight or branched C2-C6 alkenyl. Typical examples are vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-pentenyl and the like.
xe2x80x9cAlkynylxe2x80x9d includes straight or branched C2-C6 alkynyl. Typical examples are ethynyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl and the like.
xe2x80x9cAlkoxyxe2x80x9d includes straight or branched C1-C6 alkoxy. Typical examples are methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 1-ethylpropoxy, hexoxy, 1-methylpentoxy, 2-methylpentoxy, 1-ethylbutoxy and the like. The alkoxy in xe2x80x9calkoxycarbonylxe2x80x9d includes the same.
xe2x80x9cAlkanoylxe2x80x9d includes straight or branched C1-C6 alkanoyl. Typical examples are formyl, acetyl, propanoyl, butanoyl and the like. The alkanoyl in xe2x80x9calkanoylaminoxe2x80x9d include the same.
xe2x80x9cC1-C5 alkylenexe2x80x9d includes straight or branched C1-C5 alkylene. Typical examples are methylene, ethylene, propylene, trimethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, pentamethylene, 1-methyltetramethylene, 2-methyltetramethylene and the like. xe2x80x9cC1-C3 alkylenexe2x80x9d in Y includes straight or branched C1-C3 alkylene. Typical examples are methylene, ethylene and trimethylene, preferably methylene and ethylene.
The substituents of xe2x80x9csubstituted alkylxe2x80x9d include halogen, optionally substituted amino, alkoxy, alkoxycarbonyl, aryl, hydroxy, carboxy, optionally substituted carbamoyl, alkanoyl, arylcarbonyl, heteroarylcarbonyl, saturated heterocyclic group-carbonyl, alkanoylamino, alkylsulfonylamino, optionally substituted ureido, alkoxycarbonylamino, optionally substituted saturated heterocyclic group, optionally substituted sulfamoyl and the like.
Preferred examples of substituted alkyl in R1, R2, R3 and R4 are alkyls substituted by halogen(s) such as trifluoromethyl, pentafluoroethyl, 2-chloroethyl and the like.
The substituents of xe2x80x9csubstituted alkenylxe2x80x9d and xe2x80x9csubstituted alkynylxe2x80x9d include halogen, optionally substituted amino, alkoxy, alkoxycarbonyl, aryl, hydroxy, carboxy, optionally substituted carbamoyl, alkanoyl, arylcarbonyl, heteroarylcarbonyl, saturated heterocyclic group-carbonyl, alkanoylamino, alkylsulfonylamino, optionally substituted ureido, alkoxycarbonylamino, optionally substituted saturated heterocyclic group, optionally substituted sulfamoyl and the like.
Preferred examples of substituted alkynyl in R1, R2, R3 and R4 are C3-C6 1-alkynyl substituted by polar substituent(s) such as hydroxy, alkylsulfonylamino, alkanoylamino, alkylureido, oxo-saturated heterocyclic group (e.g. 2-oxo-1-imidazolodinyl, 2-oxo-1,3-oxazolin-3-yl), optionally substituted carbamoyl and the like. The examples include 4-carbamoyl-1-butynyl, 4-alkylcarbamoyl-1-butynyl, 4-dialkylcarbamoyl-1-butynyl, 4-morpholinocarbonyl-1-butynyl, xe2x80x94Cxe2x89xa1Cxe2x80x94(CH2)kxe2x80x94Q, wherein k and Q are as defined above
xe2x80x9cArylxe2x80x9d includes C6-C10 aryl. Typical examples are phenyl, 1-naphthyl, 2-naphthyl and the like. The aryl in xe2x80x9carylcarbonylxe2x80x9d includes is the same.
xe2x80x9cHeteroarylxe2x80x9d includes 5- to 7-membered mono- or bi-cyclic heteroaryl containing 1 to 3 atoms of nitrogen, sulfur and/or oxygen atoms. Typical examples include 5- to 7-membered mono-cyclic heteroaryl containing 1 to 3 atoms of nitrogen, sulfur and/or oxygen atoms such as pyridyl, pyridazinyl, isothiazolyl, pyrrolyl, furyl, thienyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, isothiazolyl, triazinyl, triazolyl, imidazolidinyl, oxadiazolyl, triazolyl, triazinyl, tetrazolyl and the like; 5- to 7-membered bi-cyclic heteroaryl containing 1 to 3 atoms of nitrogen, sulfur and/or oxygen atoms such as indolyl, chromenyl, quinolyl, isoquinolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzotriazolyl, benzimidazolyl and the like; and the like. The heteroaryl in xe2x80x9cheteroarylcarbonylxe2x80x9d includes the same.
xe2x80x9cCycloalkylxe2x80x9d includes C3-C8 cycloalkyl. Typical examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
xe2x80x9cCycloalkanexe2x80x9d includes C3-C8 cycloalkane. Typical examples are cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane and the like.
xe2x80x9cSaturated heterocyclic ringxe2x80x9d includes 5- to 7-membered mono-cyclic saturated heterocyclic rings containing 1 to 3 atoms of nitrogen, sulfur and/or oxygen atoms. Typical examples include 5-membered mono-cyclic saturated heterocyclic rings containing 1 to 3 atoms of nitrogen, sulfur and/or oxygen atoms such as tetrahydrofuran, pyrrolidine, pyrazoline, thiazolidine, oxazolidine and the like; 6-membered mono-cyclic saturated heterocyclic rings containing 1 to 3 atoms of nitrogen, sulfur and/or oxygen atoms such as piperidine, morpholine, thiamorpholine, piperazine and the like; 7-membered mono-cyclic saturated heterocyclic rings containing 1 to 3 atoms of nitrogen, sulfur and/or oxygen atoms such as perhydroazepine and the like; and the like.
xe2x80x9cSaturated heterocyclic groupxe2x80x9d is a radical formed by removing hydrogen from saturated heterocyclic ring. The saturated heterocyclic group in xe2x80x9csaturated heterocyclic group-carbonylxe2x80x9d includes the same.
The substituent of xe2x80x9csubstituted arylxe2x80x9d, xe2x80x9csubstituted phenylxe2x80x9d, xe2x80x9csubstituted 2-naphthylxe2x80x9d, xe2x80x9csubstituted heteroarylxe2x80x9d, xe2x80x9csubstituted cycloalkylxe2x80x9d, xe2x80x9csubstituted cycloalkanexe2x80x9d, xe2x80x9csubstituted saturated heterocyclic ringxe2x80x9d and xe2x80x9csubstituted saturated heterocyclic groupxe2x80x9d include halogen, aryl, heteroaryl, optionally substituted alkyl, alkenyl, alkynyl, optionally substituted amino, cyano, nitro, hydroxy, mercapto, alkoxy, alkanoyl, alkoxycarbonyl, carboxy, optionally substituted sulfamoyl, optionally substituted carbamoyl, alkylsulfamoylamino, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, alkanoylamino and the like. The substituent of xe2x80x9csubstituted saturated heterocyclic ringxe2x80x9d and xe2x80x9csubstituted saturated heterocyclicric groupxe2x80x9d also includes oxo. Examples of the xe2x80x9coxo-saturated heterocyclic ringxe2x80x9d and xe2x80x9coxo-saturated heterocyclic groupxe2x80x9d include oxo-5-membered saturated heterocyclic rings or groups such as pyrrolidinone(yl), thiazolidinone(yl), 2-oxo-1,3-oxazoline(yl), 2-oxo-imidazolidine(yl) and the like; oxo-6-membered saturated heterocyclic rings or groups such as piperidinone(yl) and the like.
Preferred examples of substituents of xe2x80x9csubstituted arylxe2x80x9d and xe2x80x9csubstituted heteroarylxe2x80x9d in R5 are halogen, alkoxy, alkyl substituted by halogen(s) and the like, especially chlorine, fluorine, methoxy, trifluoromethyl and the like.
xe2x80x9cHalogenxe2x80x9d includes fluorine, chlorine, bromine and iodine.
The substituent of xe2x80x9csubstituted aminoxe2x80x9d includes alkyl optionally substituted by hydroxy or alkoxy, and the like. Amino may be substituted by two substituents.
The substituent of xe2x80x9csubstituted sulfamoylxe2x80x9d, xe2x80x9csubstituted carbamoylxe2x80x9d and xe2x80x9csubstituted ureidoxe2x80x9d includes alkyl optionally substituted by hydroxy or alkoxy, and the like. Sulfamoyl, carbamoyl and ureido may be substituted by two substituents. When sulfamoyl, carbamoyl or ureido is substituted by two substituents, the two substituents may be taken together with adjacent nitrogen atom to form saturated heterocyclic ring such as morpholine and the like.
xe2x80x9cProdrugxe2x80x9d includes prodrugs described in Chemistry and Industry, 1980, 435; Advanced Drug Discovery Reviews 3, 39(1989). The typical examples are biohydrolyzable esters such as acyloxymethyl esters, glycolates, lactates and morpholinoethyl ester of carboxyl group; hemiglutarates of phenolic hydroxyl group; N-morpholinomethyl amides; N-acyloxymethyl amines; N-ayloxyalkoxycarbonylamines.
The oxindole derivative or a prodrug thereof may be in the form of pure optical isomer, partially purified optical isomer, racemate, mixture of diastereomers or the like. Preferred optical isomers of the oxindole derivatives are the optical isomers, of which the configurations at the 3rd position are equivalent to that of (+)-1-diethylaminoethyl-4-trifluoromethyl-6-carbamoyl-3-hydroxy-3-(2-chlorophenyl)oxindole. The optical isomers are usually distinguishable from their retention times in HPLC on a Chiralpak OD(trademark) with isopropanol/hexane as the eluent. The referred optical isomer is usually eluted later than its enantiomer.
Pharmaceutically acceptable salts of the oxindole derivatives or a prodrug thereof include salts with inorganic acids and salts with organic acids. Typical examples of the salts with inorganic acids are the hydrochloride, hydrobromide, nitrate, sulfate, phosphate salts and the like. Typical examples of the salts with organic acids are the formate, acetate, trifluoroacetate, propionate, lactate, tartrate, oxalate, fumarate, maleate, citrate, malonate, methanesulfonate, benzenesulfonate salts and the like. In case that the oxindole derivatives have acidic group(s) such as carboxyl and the like, salts thereof with bases may be formed. The salts include salts with organic bases such as the arginine, lysine, triethylammonium salts and the like; salts with inorganic bases such as the alkaline metal (sodium, potassium, etc.), alkaline earth metal (calcium, barium, etc.), ammonium salts and the like. The oxindole derivative or pharmaceutically acceptable salt thereof may be in the form of a solvate such as a hydrate and the like. The oxindole derivative of Formula 1 can be produced for example by the following methods. 
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, Z, n and m are as defined above. X is chlorine, bromine, iodine, methanesulfoxy or toluenesulfoxy; M is lithium, magnesium bromide, magnesium iodide or magnesium chloride; W3 is hydrogen, alkyl or xe2x80x94Yxe2x80x94CON(R10)R11 wherein R10 and R11 are as defined above.
Compound (4) is produced by reacting isatin derivative (2) with compound (3) in the presence of a base. The reaction can be carried out according to conventional conditions of N-alkylation reaction. The base includes an alkaline hydride such as sodium hydride, potassium hydride and the like; alkaline amide such as sodium amide, lithium amide and the like; alkaline alkoxide such as potassium t-butoxide, sodium methoxide and the like; and the like. The amount of the base is usually 1 to 10 equivalents, preferably 1.5 to 5 equivalents, per equivalent of the isatin derivative (2). When a salt of compound (3) such as the hydrochloride and the like is used, the corresponding equivalents of the base may be added in surplus. The amount of compound (3) is usually 1 to 3 equivalents, preferably 1.2 to 2 equivalents, per equivalent of the isatin derivative (2). The reaction solvent includes an inert organic solvent such as tetrahydrofuran (THF), N,N-dimethylformamide (DMF) and the like. The reaction temperature may be in the range of 0xc2x0 C. to the boiling point of the solvent, preferably in the range of room temperature to 80xc2x0 C.
Compound (6) is produced by reacting compound (4) with compound (5). The reaction of compound (4) with compound (5) can be carried out by conventional methods. The amount of compound (5) is usually 1 to 2 equivalents per equivalent of compound (4). The reaction solvent includes ethers such as diethyl ether, THF and the like. The reaction temperature may be in the range of xe2x88x9278xc2x0 C. to room temperature.
The hydroxy group of compound (6) may be converted to an amino group, if needed. Chlorination of compound (6) with thionyl chloride, followed by azidation and reduction affords the corresponding amine. The chlorination is usually carried out without solvents at the temperature between room temperature and 50xc2x0 C. The azidation is for example performed using alkaline azide such as sodium azide in the presence of a base such as triethylamine in an inert solvent such as THF and DMF at the temperature between room temperature and 80xc2x0 C. The reducing agent includes tin chloride. The reaction solvent includes alcohols such as methanol and ethanol. The reaction temperature may be in the range of room temperature to the boiling point of the solvent.
Oxindole derivative (7) can be produced by introducing alkyl or xe2x80x94Yxe2x80x94CON(R10)R11 wherein R10 and R11 are as defined above to compound (6) or the corresponding amine, if needed. Introduction of alkyl or xe2x80x94Yxe2x80x94CON(R10)R11 can be carried out by conventional methods, for example, reaction with alkyl halide, X1xe2x80x94Yxe2x80x94CON(R10)R11 wherein R10 and R11 are as defined above; X1 is chlorine, bromine, iodine, methanesulfonyl or toluenesulfonyl, or R10xe2x80x94NCO wherein R10 is as defined above, in the presence or absence of a base. The base includes an alkaline hydride such as sodium hydride, potassium hydride and the like; an alkaline amide such as sodium amide, lithium amide and the like; organic base such as triethylamine, ethyldiisopropylamine and the like. The amount of the base is usually 1 to 10 equivalents per equivalent of compound (6) or the corresponding amine. The amount of the alkyl halide, X1xe2x80x94Yxe2x80x94CON(R10)R11 or R10xe2x80x94NCO is usually 1 to 10 equivalents per equivalent of compound (6) or the corresponding amine. The reaction solvent includes inert solvents such as THF, DMF and the like. The reaction temperature may be in the range of 0xc2x0 C. to the boiling point of the solvent, preferably in the range of room temperature to 80xc2x0 C. 
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, n, m, X, M and W3 are as defined above.
Compound (8) is produced by reacting isatin derivative (2) and compound (5) by the same method as that in the reaction of compound (4) with compound (5). The hydroxyl group of compound (8) may be converted to an amino group by the same method as that in conversion of hydroxyl group of compound (6). Then, oxindole derivatives (7) and (9) can be produced by reacting compound (8) with compound (3) by the same method as that in the reaction of isatin derivative (2) with compound (3), followed by introduction of alkyl or xe2x80x94Yxe2x80x94CON(R10)R11 wherein R10 and R11 are as define above, if needed. This reaction normally produces the oxindole derivative (9) mainly.
Isatin derivative (2) can be prepared for example as below.
Method for Preparing Isatin Derivatives (Method C) 
wherein R1, R1, R3 and R4 are as defined above.
Isatin derivative (2) can be prepared according to Sandmeyer""s method (Org. Synth., Coll. Vol. I, 321(1941)). Isatin derivative (2) is prepared by reacting aniline derivative (10) with chloral hydrate and hydroxylamine in water under reflux to give compound (11), followed by treating the compound with acid and then with water. The acid includes conc. sulfuric acid, polyphosphoric acid and the like. The acid may be used as a solvent preferably. The temperature in the treatment with acid may be in the range of 50 to 100xc2x0 C. The treatment with water is performed by adding the reaction mixture into water. The temperature of the treatment with water is preferably in the range of 0xc2x0 C. to room temperature. Ice may be used in place of the water, because the treatment makes a lot of heat.
Isatin derivative (2) is prepared by reacting Aniline derivative (10) with oxalyl chloride, followed by intramolucular Friedel-Crafts reaction. These two reactions may also be done all at once in the same vessel. The reaction solvent includes halogenated solvents such as methylene chloride, 1,2-dichloroethane and the like. The reaction may be carried out without solvents. In the Friedel-Craft""s reaction, Lewis acid may be added. The Lewis acid includes aluminum chloride and the like.
Method for Preparing Isatin Derivative (Method D) 
wherein R1, R2, R3 and R4 are as defined above; R14 and R15 are independently alkyl.
Isatin derivative (2) can be prepared according to Gassman""s method (J. Am. Chem. Soc., 96, 5508(1974)). Compound (12) is prepared by chlorination of aniline derivative (10) followed by adding compound: R14SCH2CO2R15 and then a base. The reaction solvent includes halogenated solvents such as methylene chloride, 1,2-dichloroethane and the like. The chlorination agent includes sulfuryl chloride, t-butoxy chloride and the like. The temperature of the chlorination and the addition of compound: R14SCH2CO2R15 may be in the range of xe2x88x9220 to xe2x88x9278xc2x0 C. The base includes organic bases such as triethylamine and the like. The addition of a base may be carried out by warming the reaction mixture to room temperature and keeping the mixture at the temperature.
Compound (13) is produced by treating compound (12) with an acid. The acid includes hydrochloric acid, sulfuric acid, methanesulfonic acid and the like. The reaction temperature may be room temperature. This reaction may be carried out in the same vessel of the previous reaction successively.
Compound (2) is produced by oxidation of compound (13). The oxidizing agent includes copper(II) oxide and the like. The reaction temperature may be in the range of room temperature to the boiling temperature of the solvent. The reaction solvent includes an inert organic solvent such as acetone, acetonitrile and the like.
Method for Preparing Isatin Derivative (Method E) 
wherein R1, R2, R3 and R4 are as defined above; R15 and R16 are independently alkyl.
Isatin derivative (2) can be prepared by Reisert reaction. For example, Reisert reaction of nitrotoluene (14) with dialkyl oxalate in the presence of metal alkoxide in an alcoholic solvent provides ketoester (15) (J. Am. Chem. Soc., 78, 221 (1956)). Suitable combinations of the dialkyl oxalate, metal alkoxide and alcoholic solvent are dimethyl oxalate-sodium methoxide-methanol, dimethyl oxalate-potasium methoxide-methanol and diethyl oxalate-sodium ethoxide-ethanol. Treating ketoester (15) with aqueous hydrogen peroxide in the presence of acid such as perchloric acid (J. Org. Chem., 16, 1785 (1951)) followed by methylation using methanol-hydrogen chloride or thionyl chloride affords ester (16). Reduction of the nitro group with Fe-acetic acid, aqueous titanium trichloride or tin(II) chloride forms oxindole (17) (Synthesis, 1993, 51). Two steps conversion of oxindole (17) into isatin (2) are effected by treating pyridinium tribromide followed by hydrolysis using acid such as hydrogen bromide (Tetrahedron Lett., 39, 7679 (1998)).
In the above reactions, functional groups in each compound may be protected if needed. The protective groups include the well known protective groups (Protective Groups in Organic Synthesis, T. W. Greene, A Wiley-Interscience Publication (1981) etc.) and the like.
Oxindole derivative (1) produced according to the above methods may be mixture of isomers. In that case, each isomer can be isolated by a suitable method such as silica chromatography and the like at the final stage or an intermediate stage.
Optical isomers of oxindole derivative (1) may be obtained by conventional optical resolution methods such as recrystallization of salts thereof with an optical acid such as tartaric acid and the like.
Prodrug of the oxindole derivative (1) may be obtained by conventional methods (as described in Chemistry and Industry, 1980, 435; Advanced Drug Discovery Reviews 3, 39(1989)).
The pharmaceutically acceptable salt of the oxindole derivative (1) or a prodrug thereof can be formed by mixing the oxindole derivative (1) or a prodrug thereof with a pharmaceutically acceptable acid such as hydrogen chloride, citric acid, methanesulfonic acid and the like in a solvent such as water, methanol, ethanol, acetone and the like.
Specifically preferred examples of the oxindole derivatives are:
1-(2-Diethylaminoethyl)-4-trifluoromethyl-6-carbamoyl-3-hydroxy-3-(2-chloro-3-pyridyl)oxindole,
1-(2-Diethylaminoethyl)-4-trifluoromethyl-6-carbamoyl-3-hydroxy-3-(2-chloro-3-thienyl)oxindole,
1-(2-Diethylaminoethyl)-4-trifluoromethyl-6-carbamoyl-3-hydroxy-3-(5-indolyl)oxindole,
1-(2-Diethylaminoethyl)-4-trifluoromethyl-6-[3-(3-methyl-2-oxo-1-imidazolidinyl)-1-propynyl]-3-hydroxy-3-(2-chlorophenyl)oxindole,
1-(2-Diethylaminoethyl)-4-trifluoromethyl-6-[4-(3-methyl-2-oxo-1-imidazolidinyl)-1-butynyl]-3-hydroxy-3-(2-chlorophenyl)oxindole,
1-(2-Diethylaminoethyl)-4-trifluoromethyl-6-[4-dimethylcarbamoyl-1-butynyl]-3-hydroxy-3-(2-chlorophenyl)oxindole,
1-(2-Diethylaminoethyl)-4-trifluoromethyl-6-[5-dimethylcarbamoyl-1-pentynyl]-3-hydroxy-3-(2-chlorophenyl)oxindole,
1-(2-Diethylaminoethyl)-4-trifluoromethyl-6-dimethylcarbamoylethynyl-3-hydroxy-3-(2-chlorophenyl)oxindole,
1-(2-Diethylaminoethyl)-4-trifluoromethyl-6-carbamoylethynyl-3-hydroxy-3-(2-chloro-4-bromophenyl)oxindole,
1-(2-Diethylaminoethyl)-4-trifluoromethyl-6-(2-carbamoylethenyl)-3-hydroxy-3-(2-chloro-4-bromophenyl)oxindole,
1-(2-Diethylaminoethyl)-4-trifluoromethyl-6-(2-carbamoylethyl)-3-hydroxy-3-(2-chloro-4-bromophenyl)oxindole,
1-(2-Diethylaminoethyl)-4-trifluoromethyl-6-(4-amino-1-butynyl)-3-hydroxy-3-(2-chlorophenyl)oxindole,
1-(2-Diethylaminoethyl)-4-trifluoromethyl-6-(4-acetamino-1-butynyl)-3-hydroxy-3-(2-chlorophenyl)oxindole,
1-(2-Diethylaminoethyl)-4-trifluoromethyl-6-(5-carboxy-1-pentynyl)-3-hydroxy-3-(2-chlorophenyl)oxindole,
1-(2-Diethylaminoethyl)-4-trifluoromethyl-6-sulfamoyl-3-hydroxy-3-(2-chlorophenyl)oxindole,
1-(2-Diethylaminoethyl)-4-trifluoromethyl-6-methylsulfamoyl-3-hydroxy-3-(2-chlorophenyl)oxindole,
1-(2-Diethylaminoethyl)-4-trifluoromethyl-6-dimethylsulfamoyl-3-hydroxy-3-(2-chlorophenyl)oxindole,
1-(2-Diethylaminoethyl)-4-trifluoromethyl-6-(4-sulfamoyl-1-butynyl)-3-hydroxy-3-(2-chlorophenyl)oxindole,
1-(2-Diethylaminoethyl)-4-trifluoromethyl-6-carbamoyl-3-hydroxy-3-(1-naphthyl)oxindole,
1-(2-Diethylaminoethyl)-4-trifluoromethyl-7-carbamoyl-3-hydroxy-3-(2-chlorophenyl)oxindole,
1-(2-Diethylaminoethyl)-6-carbanoyl-3-hydroxy-3-(2-chlorophenyl)oxindole,
1-(2-Diethylaminoethyl)-4-methyl-6-carbamoyl-3-hydroxy-3-(2-chlorophenyl)oxindole,
1-(2-Diethylaminoethyl)-4-methoxy-6-carbamoyl-3-hydroxy-3-(2-chlorophenyl)oxindole,
1-(2-Diethylaminoethyl)-4-fluoro-6-carbamoyl-3-hydroxy-3-(2-chlorophenyl)oxindole,
1-(2-Diethylaminoethyl)-4-cyano-6-carbamoyl-3-hydroxy-3-(2-chlorophenyl)oxindole,
1-(2-Diethylaminoethyl)-4-hydroxy-6-carbamoyl-3-hydroxy-3-(2-chlorophenyl)oxindole,
1-(2-Diethylaminoethyl)-5-trifluoromethyl-6-carbamoyl-3-hydroxy-3-(2-chlorophenyl)oxindole,
1-(2-Diethylaminoethyl)-5-chloro-6-carbamoyl-3-hydroxy-3-(2-chlorophenyl)oxindole,
1-(2-Diethylaminoethyl)-4-trifluoromethyl-5-chloro-6-carbamoyl-3-hydroxy-3-(2-chlorophenyl)oxindole,
1-(2-(2-Piperidinyl)ethyl-4-trifluoromethyl-6-carbamoyl-3-hydroxy-3-(2-chlorophenyl)oxindole,
1-(2-(2-Pyrrolidinyl)ethyl)-4-trifluoromethyl-6-carbamoyl-3-hydroxy-3-(2-chlorophenyl)oxindole,
1-(2-(N-methyl-2-pyrrolidinyl)ethyl)-4-trifluoromethyl-6-carbamoyl-3-hydroxy-3-(2-chlorophenyl)oxindole,
1-(2-Piperidinylmethyl)-4-trifluoromethyl-6-carbamoyl-3-hydroxy-3-(2-chlorophenyl)oxindole,
1-(3-Amino-3-methylbutyl)-4-trifluoromethyl-6-carbamoyl-3-hydroxy-3-(2-chlorophenyl)oxindole,
1-(3-Aminobutyl)-4-trifluoromethyl-6-carbamoyl-3-hydroxy-3-(2-chlorophenyl)oxindole,
1-(4-Dimethylamino-3,3-dimethylbutyl)-4-trifluoromethyl-6-carbamoyl-3-hydroxy-3-(2-chlorophenyl)oxindole,
1-(2-Diethylaminoethyl)-4-trifluoromethyl-6-carbamoyl-3-hydroxy-3-(2,3-dichlorophenyl)oxindole,
1-(2-Diethylaminoethyl)-4-trifluoromethyl-6-carbamoyl-3-hydroxy-3-(2-chloro-4-methoxyphenyl)oxindole,
1-(2-Diethylaminoethyl)-4-trifluoromethyl-6-carbamoyl-3-hydroxy-3-(2-chloro-4-bromophenyl)oxindole, and
1-(2-Diethylaminoethyl)-4-trifluoromethyl-6-carbamoyl-3-hydroxy-3-(2,3,4-trichlorophenyl)oxindole.
The oxindole derivatives of the present invention have effects and usage similar to those of growth hormone, because the oxindole derivatives can stimulate the release of growth hormone from the pituitary. Examples of the growth hormone""s effects and usage are as follows:
stimulation of growth hormone release in the elderly; treating growth hormone deficient adults; prevention of catabolic side effects of glucocorticoids; prevention and treatment of osteoporosis; stimulation of the immune system; acceleration of wound healing; accelerating bone fracture repair; treatment of growth retardation; treating acute or chronic renal failure or insufficiency; treatment of physiological short stature including growth hormone deficient children and short stature associated with chronic illness; treatment of obesity and growth retardation associated with obesity; treating growth retardation associated with the Prader-Willi syndrome and Turner""s syndrome; accelerating the recovery and reducing hospitalization of burn patients or following major surgery such as gastrointestinal surgery; treatment of intrauterine growth retardation, skeletal dysplasia, hypercortisolism and Cushing""s syndrome; induction of pulsatile growth hormone release; replacement of growth hormone in stressed patients; treatment of osteochondrodysplasias, Noonan""s syndrome, schizophrenia, depressions, Alzheimer""s disease, delayed wound healing and psychosocial deprivation; treatment of pulmonary dysfunction and ventilator dependency; attenuation of protein catabolic responses after major surgery; treating malabsorption syndromes; reducing cachexia and protein loss due to chronic illness such as cancer or AIDS; accelerating weight gain and protein accretion in patients on TPN (total parenteral nutrition); treatment of hyperinsulinemia including nesidioblastosis; adjuvant treatment for ovulation induction and to prevent and treat gastric and duodenal ulcers; stimulation of thymic development; prevention of the age-related decline of thymic function; adjunctive therapy for patients on chronic hemodialysis; treatment of immunosuppressed patients; enhancing antibody response following vaccination; improvement in muscle strength and mobility in the frail elderly; maintenance of skin thickness, metabolic homeostasis, renal homeostasis in the frail o elderly; stimulation of osteoblasts, bone remodelling and cartilage growth in the frail elderly; treatment of neurological diseases such as peripheral and drug induced neuropathy, Guillian-Barre Syndrome, amyotrophic lateral sclerosis, multiple sclerosis, cerebrovascular accidents and demyelinating diseases; stimulation of the immune system in companion animals; treatment of disorders of aging in companion animals; growth promotion in livestock; stimulation of wool growth in sheep; and the like.
In particular, the oxindole derivatives are useful for treating medical disorders resulting from a deficiency in growth hormone.
The oxindole derivatives of the present invention may be applicable to not only humans but also various non-human mammals such as mice, rats, dogs, cows, horses, goats, sheep, rabbits, pigs and the like.
The oxindole derivative of the present inventionmay be administered orally or parenterally (intramuscularly, intravenously, subcutaneously, percutaneously, intranasally, by suppository, by eye drops, by injection into brain). Pharmaceutical forms include generally acceptable forms, for example, powders, granules, fine granules, tablets, capsules, pills, syrups, suspensions, injections such as solutions, emulsions, suppository for administration through the rectum, dermal preparations (ointments, creams, lotions etc.) and the like.
These compositions can be prepared by the conventional methods using conventional carriers or diluents. The solid compositions such as tablets can be prepared by mixing the active compound with pharmaceutically acceptable conventional carriers or excipients such as lactose, sucrose, corn starch or the like; binders such as hydroxypropylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose or the like; disintegrating agents such as sodium carboxymethylcellulose, sodium starch glycolate or the like; lubricants such as stearic acid, magnesium stearate or the like; or preservatives or the like. For parenteral administration such as solutions and suspensions, the active compound can be dissolved or suspended in a physiologically acceptable carrier or diluent such as water, saline, oil, dextrose solution or the like, which may contain auxiliary agents such as pH adjusters, buffers, stabilizers, solubilizers, emulsifiers, salts for influencing osmotic pressure and the like, if desired.
The dose and the frequency for administration of the oxindole derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof generally varies depending on the species to be cured, the administration route, the severity of the symptoms, the body weight and the like. The oxindole derivative, a prodrug thereof and a pharmaceutically acceptable salt thereof are usually administered to an adult (body weight: 60 kg) in a dose of about 1 mg to about 1 g, preferably about 1 mg to about 200 mg, more preferably about 5 mg to about 50 mg per day in one portion or several portions. They may be also administered once in 2 days to 1 week. No toxic effects were obserbed at therapeutic doses.